ABSTRACT ? ARTFL LEFFTDS Longitudinal FTLD: Project 1 Frontotemporal lobar degeneration (FTLD) is the overall term for a group of devastating neurodegenerative disorders that have a profound effect on the lives of patients and their families. Research in FTLD is entering an exciting period as potential disease-modifying drugs are being developed. One highly attractive approach for therapy is to start treatment before symptoms occur. However, FTLD is currently almost always diagnosed long after symptoms have begun, when the disease has already had profound effects on the brain. About twenty percent of FTLD is due to autosomal dominant mutations, most commonly in the MAPT, GRN, or C9orf72 genes (familial, or f-FTLD). Mutation carriers can be identified before the onset of dementia, and are therefore critical for studies that would seek to delay or prevent symptoms. Intervention studies in f-FTLD will require unique approaches for tracking the effects of treatment. First, they must choose measures that demonstrate that an intervention is resulting in clinical benefit, even in people who are experiencing few if any symptoms. Second, they must show that the treatment prevents or delays the onset of symptoms. However, the age when a mutation carrier will develop dementia varies dramatically in f-FTLD, and there are no reliable markers for predicting age of onset. Without such predictive tools, it is impossible to target patients who are approaching symptom onset and calculate how many people would be needed for a study of symptom prevention. The overall goal of this project is to prepare for clinical trials in f-FTLD by developing better methods for selecting participants and for tracking disease burden to demonstrate treatment effects. The project will pursue the following specific aims: 1) To identify the best clinical and imaging measures for tracking disease burden in mutation carriers who are asymptomatic (FTLD-CDR=0), or mildly symptomatic (FTLD- CDR=0.5), 2) To develop a multimodal risk score to predict worsening symptoms in asymptomatic or mildly symptomatic mutation carriers using baseline clinical, genetic, protein biomarker and imaging data, and 3) To quantify the value of tracking change in cortical volume over one year for predicting future worsening of symptoms in asymptomatic or mildly symptomatic mutation carriers.